In September, 2009, the Leonberger Club of Great Britain held its annual health seminar. Part one of the event was a discussion on Anal Furunculosis, its diagnosis and treatment options. The following article is based on the video record of that presentation. The video is available in DVD format from the LCGB shop

Dr. Brian Catchpole Veterinary Immunologist Royal Veterinary College

Clinical Signs of AF.

Dr. Catchpole began his talk by describing the clinical signs of AF, the initial signs of whichare likely to include localised irritation, discomfort and straining while passing motions. There may be blood present in the stool. Constipation and or diarrhoea may also be present.

He then showed a series of graphic images of the anal region of AF affected dogs, showing clearly the two forms of presentation. These are generally either large, ulcerated surface wounds, smaller fistula openings, or a combination of the two. He pointed out that, although the ulcerative form of the illness looks far worse on the surface, it is in fact the fistulous form that is much more serious, as the surface lesion is just the end of a much deeper channel, or sinus, that extends far alongside the dog’s rectum, and can actually perforate the colon deep within the dog, leading to a much grater risk of systemic illness. The fistulous form is also the more painful for the affected dog and the least responsive to treatment.

A disease of the Immune System.

Research has focused on finding out the cause of all this tissue damage. A type of enzyme produced naturally by the body called Matrix-Metalloproteinase (MMP) is present in AF cases, andalso occurs in other immune system diseases which lead to tissue destruction, such a rheumatoid arthritis where the cartilage deteriorates. There are three major types of these MMP proteins that have been examined, MMP 2, MMP 9 and MMP 13. The first, MMP 2, is the beneficial form of the enzyme found in tissue regeneration, where it clears out damaged or diseased tissues in preparation for natural healing. It is therefore a marker for natural tissue repair. MMP 9 and 13 are harmful forms of the enzymes, produced in auto-immune disorders, where there is actual deterioration of otherwise healthy tissue. In AF affected dogs, these two harmful MMP enzymes are commonly over-abundant.

Understanding the disease.

Further understanding of the role played by these proteins has lead to various approaches for treating AF. There is an antibiotic called Doxycycline, which, in addition to fighting off secondary bacteriological infections has a side effect of inhibiting MMP enzymes. Doxycycline therefore potentially has two beneficial effects.

Dr. Catchpole shared a few facts to help emphasis how the outward signs of AF are only the “tip of the iceberg”. 50% of dogs with AF also have colitis. Internal examination will show that ulceration is also commonly present within the large bowel. This explains the diarrhoea that usually accompanies this illness.It is a disease of the large intestine, not just the anus. The obvious nature of the illness makes diagnosis relatively straight forward. Effective treatment is the challenge.

Past investigations have tried to understand the cause of this illness. Some assumed that it started with an infection of the anal glands. Some have suggested that the low tail carriage in certain breeds made them more likely to fall victim to it, assuming that the damp, airless environment around the anus would make infection more likely. Some have also looked for years for a specific type of bacteria or fungus that might be responsible. Although any one of these may be contributing factors, it is now believed that none of them are the main cause of the illness.

An immune-mediated disease.

In the past, AF was commonly considered to be a “surgical disease”, meaning that radical surgical intervention was at one time the norm, including cutting out or freezing diseased tissues, surgical resection of fistulas, and removal of the anal sacs. This usually produced poor results and common recurrence of the illness, often leaving the dog worse off. It is now primarily considered a “medical disease”, meaning that efforts now focus on addressing the process leading to tissue destruction, rather than simply repairing the damage. This shift in focus has largely come about as a result of the drug ciclosporin, also marketed as Atopica ™.

This represents a big shift in approach, as most vets once blamed a weak immune system (immunodeficiency) for the illness, and this medication is actually immunosuppressive, meaning it turns down the body’s immune response, rather than strengthen it. The response to ciclosporin therapy showed clearly that Anal Furunculosis is an immune-mediated disease. “A hyper-sensitivity of the immune system”.

Treatment options.

Dr. Catchpole spoke about various dosage levels when using this drug. The RVC prescribes 5 mg/kg of Atopica, twice a day, for 4 weeks. They get good results with this. It is quite a high dose initially, and this is an expensive drug, which can be a big problem for many owners. In their experience, using lower doses “tends to mean that the disease goes on for longer”. Therefore, using the recommended dose is likely to sort the dog out faster and for what would, in the end, be the same cost as would be the case for prolonged treatment at a lower dosage. One way to try and reduce the cost of the ciclosporin is through the use of another drug called Ketoconazole, which is actually an anti-fungal drug which has the additional property of slowing down the degradation of ciclosporin in the animal’s liver. This makes the ciclosporin last longer, which means you can reduce the actual dose to 1 to 2 mg/kg, twice a day. Another medication is an immunosuppressive cream called Tacrolimus, marketed as Protopic, which can also help clear up AF lesions. The challenge is getting it into the deep fistulas. The RVC is currently looking into a new delivery method using “Micro-spheres” that can be loaded with medication and inserted into the tracts, where they can then slow-release their medication directly within the fistula.

The RVC treatment plan is to start a dog on ciclosporin, 5 mg/kg twice daily for four weeks. The dog is then examined again at the end of the 4 weeks. If it has shown a complete response, it is put on a reduced maintenance dose and eventually taken off the drug all together. If the initial four weeks of medicatio results in only a partial response, (often seen in the fistulous cases), they will refer the dog for surgical removal of diseased tissue, and then start to reduce the drug in the same manner.

The underlying causes of AF.

As an immunologist, Dr. Catchpole is looking for patterns of illness that may indicate a more systemic defect. At the RVC, most German Shepherd Dogs that he sees either have AF, Inflammatory Bowel Disease, or Deep Pyoderma (skin disease). In Australian cases, they often also see Systemic Aspergillosis, which is a susceptibility to one of the most common funguses in the world. This can lead to severe disease throughout the body. This pattern of illness suggests a malfunction in the immune system’s response to common environmental germs. This is probably why no single germ or bacteria has ever been found to be responsible.

Dr. Catchpole then presented a short and very clear explanation at the cellular level of the normal functioning of the immune system, how it malfunctions and how the action of ciclosporin interacts with it, which is not covered in this summary, but well worth viewing in the full DVD.

While ciclosporin is a useful drug for its ability to calm down an out of control immune response- which is what is generating most of the tissue damage in these illnesses- it does not address the underlying cause of these diseases. This is why relapse is so common with AF and related illnesses. Ciclosporin does not cure the disease, it treats the flair-ups that occur because of it.

Breed susceptibility.

AF is found more commonly in some breeds, with German Shepherd dogs being one of the most common. It is known that GSDs do have deficiencies in producing a certain immune-mediating antibody, (The IgA antibody, that forms the first line of defence in the intestine). There is also a suspected deficiency in the formation of pattern recognition receptors further within the normal immune system. This is the same as what is found in Crohn’s disease in human beings. In this human form of the disease a defective gene has been identified, which relates to the production of immune system receptors necessary to identify germs as they enter the body. A genetic analysis was done in GSDs to see if these defective receptor genes found in Crohn’s cases were also present in the canine equivalent. There are normally many different versions of these receptor genes. In a mongrel dog population with a broad genetic base, you will see a wide range present, which gives the individual a robust immune system. In the GSD, there is a stark difference because there is very nearly only one version present, rather than the wide variety seen in normal canine populations. This means the GSD as a breed has much less diversity in its ability to detect invasive germs. The immune system simply cannot recognise a wide enough range of germs and therefore cannot respond to them.Current genetic analysis of blood donations from Leonbergers is attempting to answer the question “is it the same in Leonbergers”? (This research was covered in the second presentation of the day).

He then went on to describe another piece of research that took a group of AF affected GSDs and looked at their immune cell response to certain bacteria, compared with samples drawn from a wide range of the general dog population, and the results supported the previous receptor deficiency model.

Summary.

The main points of Dr. Catchpole’s summery were:

AF is likely to be multifactorial, meaning not caused by a single thing. There are likely to be both genetic factors and environmental factors, which may include diet and the presence of certain bacteria. Having the defective genes alone may not necessarily lead to illness, but it does make it far more likely that the illness will flair up if the individual encounters certain other triggers, such as environmental bacteria that the body’s malfunctioning immune system then finds itself unable to cope with.

He called this illness a “complex genetic disorder”. There is likely to be more than one gene involved. “There may be several genes involved”. A certain combination of defective genes will likely contribute to the dog developing a susceptibility for AF, and it will take time to discover which are the key triggers for the illness. This means that it will not be possible to develop a simple genetic test to identify a single faulty gene. What may be possible is to develop a test based on genetic profiling, where for example, ten different key genes are looked for, to see how many are normal or abnormal.

Question & Answer session.

A question was asked about the use of Protopic ointment rather than Atopica tablets. Protopic ointment is generally only used at the RVC in cases that have relapsed. Their first line of treatment is always the Atopica tablet version of ciclosporin, and the ointment will often be used once the initial drug treatment has been completed, and only if there are still signs of diseased tissue present at the surface. In the case of persistent fistulas, the ointment is not effective, because it is nearly impossible to deliver it down the length of the fistula tract. In these sorts of relapses, they would turn to surgical removal of diseased tissue and the bacterial source that is likely to be lodged within it. It is the continued presence of the bacteria that is believed to be constantly triggering the immune system’s malfunction, so surgical removal from deep fistulas may be necessary.

The role of stress in triggering this disorder was asked about. Dr. Catchpole stated that in his view, there has to be a “genetic susceptibility to the illness”. Stress can be a contributing environmental factor, and it is known that stress (which produces a high cortisol hormone level) can have an impact on the immune system, through triggering natural immune suppressants within the body which may reduce the animal’s resistance to infection. Once the infection sets in, in AF cases, you will then get the exaggerated response leading to tissue destruction that characterises the disease. To summarise, a dog may be more prone to pick up infections due to stress, but it is the complete failure of the immune system to mount an appropriate response to these common germs that is the fundamental characteristic of the illness.

A question was asked about the impact of low levels of thyroid production (Hypothyroidism) and the development of AF. Dr. Catchpole stated that there is a clear impact from this sort of hormonal imbalance on the immune system, and it could certainly be another of the contributing factors that can lead to triggering the illness in an individual with the pre-existing genetic susceptibility. However, they do not at present make thyroid level checks on suspected AF cases. There needs to be care taken in determining low thyroid function, and to do it properly requires two tests, not simply the single test routinely done by most vets. A low thyroxin level can be a consequence of disease, rather than a cause of it. The second test is for TSH (Thyroid Stimulating Hormone), which would be abnormally high in a case of true hypothyroidism.

A question was asked about the cancer risk associated with prolonged use of ciclosporin and similar drugs. Dr. Catchpole cited one case where a dog that was on both ketoconazole and ciclosporin for a long time because of multiple AF relapses did develop cancer (lymphoma). But there was never any direct link shown, as the dog may well have developed cancer anyway. The immune system’s primary role is to detect abnormality in cells, be they invasive bacteria, or cancer cells generated within the body itself. This is termed “tumour surveillance”. So a poorly functioning immune system can lead to an animal being more prone to cancer. However, it is also clear that prolonged suppression of the immune system, (which is what immunosuppressant drugs do), may also lead to an increased cancer risk. This is one reason why the RVC limits the duration of ciclosporin use.

A question was asked about the use of cryosurgery to freeze and destroy the affected tissue. Dr. Catchpole’s response was not in favour of this approach, “Cryosurgery is outdated”. One potential side effect being damage to the surrounding tissues, which can lead to incontinence. He then went on to say that there are many treatment plans available, but that in the RVC’s experience, ciclosporin allows the majority of cases to tone down their over-reactive immune response and heal naturally, reducing or even eliminating the need for destructive surgical interventions. He stated again, that in his opinion it is a medical rather than surgical disease.

A question was asked about the most common age of onset, which tends to be in older animals rather than in young, although his team have seen cases in 2 and 3 year old dogs as well. There is a specific defective gene suspected of being associated with the early onset cases.

A question was asked about the role of diet in the susceptibility to AF. In the case of inflammatory bowel disease, which essentially has a sililar disease process, there are dogs that do respond to a change in diet alone, without the need for antibiotics etc. What this seems to indicate is that the immune system’s over-reaction is not being triggered by invasive germs, it is being triggered by a component in the food itself, which may influence what bacteria are present in the gut. A change in diet can lead to a change in the bacteria in the gut. It is the over-reaction that cases the disease, rather than the trigger for the over-reaction. Again, he emphasised that in their view, inflammatory bowel disease, colitis and anal furunculosis are the same disease manifesting in different ways. In other words, it is the body’s abnormal immune response that is the common factor.

Finally, a question was asked about the overall number of GSDs born in the UK every year, and what proportion of these actually fall ill with AF- in other words, how can we say that GSD are overly susceptible as a breed to this illness, given the overall large numbers of GSD out there? The answer was that, although we can’t say what proportion of GSD will fall ill with AF, we can say that of the total number of cases that the RVC sees with AF, 98% were in fact German Shepherd Dogs or direct GSD crosses, with only a small number coming from other breeds. When compared to the overall breed profile of dogs treated at the RVC for all conditions (60% of which are Labradors), the fact that 98% of AF cases are GSD or GSD crosses makes it clear that there is a breed susceptibility for the disease.